Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome

Katherine A. Waugh; Paula Araya; Ahwan Pandey; Kimberly R. Jordan; Keith P. Smith; Ross E. Granrath; Santosh Khanal; Eric T. Butcher; Belinda Enriquez Estrada; Angela L. Rachubinski; Jennifer A. McWilliams; Ross Minter; Tiana Dimasi; Kelley L. Colvin; Dmitry Baturin; Andrew T. Pham; Matthew D. Galbraith; Kyle W. Bartsch; Michael E. Yeager; Christopher C. Porter; Kelly D. Sullivan; Elena W. Hsieh; Joaquin M. Espinosa

Cell Reports (Nov 2019)

Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome

Katherine A. Waugh,
Paula Araya,
Ahwan Pandey,
Kimberly R. Jordan,
Keith P. Smith,
Ross E. Granrath,
Santosh Khanal,
Eric T. Butcher,
Belinda Enriquez Estrada,
Angela L. Rachubinski,
Jennifer A. McWilliams,
Ross Minter,
Tiana Dimasi,
Kelley L. Colvin,
Dmitry Baturin,
Andrew T. Pham,
Matthew D. Galbraith,
Kyle W. Bartsch,
Michael E. Yeager,
Christopher C. Porter,
Kelly D. Sullivan,
Elena W. Hsieh,
Joaquin M. Espinosa

Affiliations

Katherine A. Waugh: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Paula Araya: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Ahwan Pandey: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80302, USA
Kimberly R. Jordan: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Keith P. Smith: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Ross E. Granrath: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Santosh Khanal: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Eric T. Butcher: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Belinda Enriquez Estrada: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Angela L. Rachubinski: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Jennifer A. McWilliams: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Ross Minter: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Tiana Dimasi: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Kelley L. Colvin: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Dmitry Baturin: Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Andrew T. Pham: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Matthew D. Galbraith: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Kyle W. Bartsch: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Michael E. Yeager: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Christopher C. Porter: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
Kelly D. Sullivan: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Elena W. Hsieh: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Joaquin M. Espinosa: Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80302, USA; Corresponding author

Journal volume & issue: Vol. 29, no. 7
pp. 1893 – 1908.e4

Abstract

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Summary: People with Down syndrome (DS; trisomy 21) display a different disease spectrum relative to the general population, including lower rates of solid malignancies and higher incidence of neurological and autoimmune conditions. However, the mechanisms driving this unique clinical profile await elucidation. We completed a deep mapping of the immune system in adults with DS using mass cytometry to evaluate 100 immune cell types, which revealed global immune dysregulation consistent with chronic inflammation, including key changes in the myeloid and lymphoid cell compartments. Furthermore, measurement of interferon-inducible phosphorylation events revealed widespread hypersensitivity to interferon-α in DS, with cell-type-specific variations in downstream intracellular signaling. Mechanistically, this could be explained by overexpression of the interferon receptors encoded on chromosome 21, as demonstrated by increased IFNAR1 surface expression in all immune lineages tested. These results point to interferon-driven immune dysregulation as a likely contributor to the developmental and clinical hallmarks of DS. : Waugh et al. undertook deep mapping of the immune system in adults with trisomy 21, revealing global immune dysregulation reminiscent of inflammatory states, concurrent with widespread hypersensitivity to IFN-α. These data highlight immune dysregulation and IFN hyperactivity as contributors to the comorbidities more common in people with Down syndrome. Keywords: Down syndrome, trisomy 21, mass cytometry, CyTOF, immune dysregulation, single cell, interferon, JAK/STAT, autoimmunity, inflammation

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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